Pharmacokinetics Flashcards
What is grahams law
Rate of diffusion is inversely proportional to the square root of the MW of a substance
What is first pass metabolism
Where the concentration of a drug is reduced before it reaches the systemic circulation by gut/liver.
Extraction ratio?
Fraction of a drug removed by an organ on each pass through that organ
Drugs with hig extraction ratio? (>0.7)
Propanolol
Lidocaine
GTN
TCA
Opiods
Drugs with intermediate extraction ratio? (0.3-0.7)
Midazolam
More dependent on enzyme activity
Low extraction ratio drugs? (<0.3)
-Capacity dependent clearance=sensitive to protein binding/enzyme limited/senstive to changes in enzyme. Blood flow will not really affect how much extracted
EG thiopentone, phenytoin, warfarin
What is bioavailability?
The amount of drug that reaches the systemic circulation compared to that given IV
What affects bioavailability?
- absorption from whichever route
- Drug loss from gut lumen (diarrhoea/mucosa issues)
- Metabolism in gut wall/first pass
-Poor lipid solubility
-High molecular weight
WHat is distribution
TRansfer of drug dfrom site of absorption to other tissues about the body
What factors affect distribution
-Protein binding
- blood flow
MW
ionisation
conc. gradient
What is clearance
The volume of plasma cleared of drug per unit time
what is metabolism
Conversion of drugs from one form to another that can be eliminated from the body
Examples of phase one reactions
Oxudation
HYdrolysis
Reduction
What is the purpose of phase 2 reactions
Increase water solubility to allow excretion by kidneys/bile
Examples of phase 2 reactions
Conjugation with glycine/sulfate/glucuronic acid
Where are the largest quantites of Cytochrome oxidase P450 found
SER of the liver
What is elimination
The removal of drug from body (by metabolism or excretion)
What is excretion
The removal of unchanged drug or metabolites from the body ( a form of elimination)
WHat is eulers number
base of natural log, base rate of growth shared by all continually growing processes
(base rate of change of an exponential process)
FActors affecting half life?
-Increased Vd increases half life
- Decreasing clearance increases half life
Fentanyl pKA
Weak base
pKa 8.4 (entirly ionised in the stomach)
Diclofenac pKA
Weak acid, pKA of 4
Why is absorption from the small bowel more important than stomach for most oral meds?
Greater absorptive area = greater proportion of absorption
WHere can thiopental be given in the GI tract?
REctally
Why cant atracurium be given orally?
Bis-quaternary molecule that is permanently charged and not absorbed from the GI tract
Why is physostigmine better absorbed than neostigmine?
Neostigmine is quaternary and charged, physostigmine is a tertiary amine
WHat determines binding to albumin/alpha 1 acid glycoprotein?
Acidic/neutral drugs bind to albuin
Basic drugs or those with a quaternart nitrogen bind to a1a glycoprotein
Basic drugs?
Fentanyl
Lidocaine
Acidic drugs?
Ibuprofen
Neutral drugs?
DIazepam
Phenytoin
Why do amiodarone and warfarin interact?
Amiodarone inhibits CYP2C9
non depolarising muscle relaxants Vd?
SMall- charged + do not cross lipid membranes
Propofol Vd
Large- estimated at 20-60L/kg (at least 4 even with short infusions)
Essentially unionised at plasma pH + v lipid soluble
Metabolites of atracurium
Laudanosine (minor hoffman pathway)
Monoquaternary alcohol derivative (major ester hydrolysis pathway)
Enzymes showing pharmacogenetic variations
CYP2D6 (codeine)
CYP2C9 (Warfarin)
Drugs with high oral bioavailability?
Paracetamol (90)
Ibuprofen (>80)
Drugs with poor bioavailability?
Aspirin (65)
Oramorph (25)
Diclofenac (50)
What breaks down remifentanyl?
Tissue esterases (+ plasma esterase, but less important)
Why does dobutamine increase hepatic extraction of propofol?
INcreases hepatic blood flow
What enzymes are involved in propofol metabolism
CYP2B6 + CYP2C9
WHy doesnt carbamazepine increase hepatic extraction of propofol?
Induces CYP enzymes, but the hepatic ER is already almost 1
Drugs with small volumes of distribution?
Permanently charged molecules (do not distribute across lipid membranes) / lipid insoluble/rapidly metabolised/ionised at body pH
What affects drugs crossing the placenta?
Drugs that are lipid soluble cross the placenta more rapidly than drugs that are ionised at plasma pH
Drugs that are permanently charged do not cross the placenta
